However, these observations raise the issue of the potential deleterious effects of inhibiting hypertrophy. many intersections. A series of observations has pointed toward calcineurin as a key mediator of cardiac hypertrophy, and two articles in this issue of PNAS have further underscored this assertion (1, 2). Calcineurin is usually a serineCthreonine phosphatase that is activated by Ca+2-calmodulin. Calcineurin dephosphorylates nuclear Rabbit polyclonal to NGFRp75 factor of activated T cells (NFAT), which then translocates to the nucleus where it functions combinatorially with other transcription factors to activate downstream targets. A report by Molkentin have effects in the heart, if expressed. Another class of protein inhibitors of calcineurin is usually termed MCIPs (myocyte enriched calcineurin interacting proteins). MCIPs are highly expressed in striated muscle mass and are unrelated to any of the above-mentioned Angiotensin I (human, mouse, rat) inhibitors of calcineurin. Because of their enrichment in striated muscle mass, they would seem to be attractive as potential selective inhibitors of calcineurin. Of the two family members, MCIP1, and not MCIP2, is usually regulated by calcineurin activity, providing a backup means of protecting the cell from your deleterious effects of unrestrained calcineurin activity (17, 18). In the articles by Rothermel and De Windt (1, 2), genetic approaches were taken to inhibit calcineurin activity, but each study has unique aspects as well. Both used transgenic Angiotensin I (human, mouse, rat) overexpression of protein inhibitors of calcineurin, and the use of the -cardiac myosin heavy chain promoter provided cardiac-specific expression of the transgene. The inhibitors used were either truncated forms of AKAP79 and cabin-1/cain (2) or MCIP1 (1). The three inhibitors were tested for their effect on several distinct models of cardiac hypertrophy. The first was the well known hypertrophic response of the heart to -adrenergic activation, and the three protein inhibitors were found to be effective in inhibiting hypertrophy. Although wild-type animals showed 22% increase in heart/body excess weight in response to isoproterenol, MCIP1 expression limited hypertrophic growth to an 8% increase. Cabin-1/cain expression reduced hypertrophic growth from a 20% increase to 10%. The effect of cabin-1/cain activity expression was also Angiotensin I (human, mouse, rat) tested on aortic constriction of the expressing transgenic mice and also used in an acute administration of the protein inhibitors via adenovirus mediated gene transfer to the rat heart, which had been subjected to aortic constriction. Both were found to be effective. An added measure of efficacy in the paper by DeWindt em et al. /em (2) was that the authors measured calcineurin activity and showed that activity was stressed out by the peptide inhibitors. However, as they notice, you will find reservations with the calcineurin activity assay. The authors of the MCIP1 paper tested the efficacy of MCIP1 expression on the genetic model of hypertrophy and failure resulting from cardiac expression of activated calcineurin. Once again, the effect was striking in that it was similar to the effects of treatment with CsA or FK506. Is usually All Hypertrophy Bad? Of added import was the test of the effect of MCIP1 on exercise-induced hypertrophy. Desire for this experiment stems from the little that is known about the overlap of physiologic and pathologic hypertrophic pathways. It is well appreciated that exercise conditioning results in cardiac enlargement that is beneficial, whereas hypertrophy that results from a pathologic stimulus such as pressure overload can ultimately be deleterious. MCIP1 expression was shown to be effective in inhibiting exercise-induced hypertrophy. Herein lies the rub. From a basic science perspective, it is very useful to know that the calcineurin pathway is usually common, at least at some level, to both forms of hypertrophy. However, these observations raise the issue of the potential deleterious effects of inhibiting hypertrophy. Both groups reported some deleterious effects of calcineurin inhibition in their founder populations. For example, transgenic lines expressing high.